Stroke is a leading cause of death and disability, but despite extensive research, few effective treatments for acute stroke exist. Hypothermia has been shown to protect the brain and improve neurologic status after cerebral ischemia, but its mechanisms are not fully understood. We propose in this renewal application to investigate hypothermia's effect on molecular neuronal "survival pathways" using a rat model of permanent middle cerebral artery occlusion. In particular, we will study the serine/threonine kinase Akt/PKB (or "Akt") survival pathway, examining how it is modulated by hypothermia, how such modulation correlates with neuroprotection and improvement in neurologic status, and how the Akt pathway interacts with key apoptotic pathways. Because protein kinase C-d (dPKC) is involved in the disruption of Akt survival signals, we also propose to study cross-talk between the Akt pathway and dPKC activity and hypothermia's influence on JPKC-related events. Our Specific Aims are: Specific Aim 1. Explore conditions of protection by hypothermia in a model of permanent middle cerebral artery occlusion, and the effect of hypothermia on signals of the Akt survival pathway. Specific Aim 2. Examine interactions between the Akt pathway and classic apoptotic signals in normothermic and hypothermic cerebral ischemia. Specific Aim 3. Study the effect of hypothermia on activity of dPKC and dPKC 's effect on the Akt pathway. Examine neuroprotection caused by the combination of a dPKC inhibitor and hypothermia. Our preliminary data suggest that we will observe specific effects on cell death/survival pathways that will help us elucidate mechanisms underlying hypothermia's neuroprotection in the setting of cerebral ischemia. [unreadable] [unreadable]